The liver is recognized to be the most “tolerogenic organ”. Liver transplants are always accepted in mouse models and in some rat strains across complete MHC mismatches and in some outbred pigs. Transplantation of the liver in some rat strains can prevent rejection of skin, heart and kidney allografts and can in fact turn off an ongoing rejection episode. In humans antibody rejection is rare and it is recognized that chronic rejection is uncommon and some patients can accept allografts long term without immunosuppression. It is clear that tolerance in humans can be observed if bone marrow chimerism becomes established but this is rare. In the absence of chimerism it is best to think of liver tolerance as two separate but possibly linked processes namely the induction phase followed by a maintenance phase .It is know from experiments in our group and those of others that the induction of liver tolerance versus rejection occurs in the first week of transplantation. (1)During this phase liver transplantation is not due to Tregs as tolerance at this stage can not be transferred by recipient splenocytes. In fact liver transplantation tolerance during this phase is an active deletion process whereby there is an actual allograft “rejection” episode that does not lead to full blown rejection but tolerance. This process requires two mechanisms 1) Donor leucocytes leaving the allograft and activating recipient CD8 T cells in systemic lymphoid tissues but triggering their deletion; 2) Recipient CD8 cells entering the allograft, either as naïve T cells or as activated cells from systemic lymphoid tissue. These cells are partially activated but do not form CTLs .They are eliminated within the allograft by suicidal emperipolesis (hepatocyte induced degradation) or Bim dependent cell death. These processes combine and lead to effect early deletion of the CD 8 allograft response and hence tolerance and acceptance of the liver allograft.
Following acceptance of the allograft tolerance to other allografts (skin, heart kidney) also occurs and by 100 days in the rat this tolerance is then transferable by recipient splenocytes (Tregs).Thus the maintenance phase mechanisms seem quite different to the early induction phase although CD 8 T cell deletion may still occur. This maintenance phase has now been studied in humans where about 5% of adults can been seen as tolerant from the ITT perspective post transplant. If patients are highly selected by successful weaning before the withdrawal of immunosuppression then about 20-23 % of adults and perhaps up to 40% of children can be defined as tolerant (i.e. no allograft rejection when immunosuppression is withdrawn: so called Prope Tolerance)
These patients have been studied for gene signatures in PBLs and within the allograft itself that may identify tolerance before IS withdrawal. Groups in the USA and Europe have defined gene signatures enriched for Tregs, Gamma/ Delta T cells and NK cells in the tolerance signature (2,3).One group has identified a 3 gene signature in PBLs from children that may define tolerance (3).These signatures define patients many years ( > 5 Years) who may be tolerant. Challenges occur in identifying similar patterns in additional cohorts and in studying the timing of the onset of these signatures i.e. how early do they develop and what is their link to the early induction phase in experimental animals but not yet studied in humans. There are exciting times ahead in meeting these challenges.
References
Volume : 11
Issue : 6
Pages : 10
Head, Liver Immunobiology Program, Centenary Research Institute
A.W. Morrow Professor of Medicine
Director, A.W. Morrow GE/Liver Center
Director, Australian Liver Transplant Unit
Royal Prince Alfred Hospital, University of Sydney
Sydney, Australia